neuropeptide-y and Hyperlipidemias

Abnormal baroreceptor reflex sensitivity (BRS) and elevated plasma neuropeptide Y (NPY) are prevalent in diabetic patients. The present study was conducted to determine whether NPY Y1 receptor (Y1R) and NPY Y2 receptor (Y2R) contribute to the regulatin of BRS in diabetic rats.. Diabetes mellitus (DM) rats with hyperlipidemia were developed by an emulsion diet enriched with fat, sucrose and fructose followed by streptozocin (STZ). Y1R and Y2R specific antagonists (BIBP 3226 and BIIE 0246) were administered by a mini-osmotic pump. Systolic blood pressure (SBP), heart rate (HR), BRS and heart functions, as well as the plasma NPY and lipid level were measured after treatment for 4 weeks.. Both BIBP 3226 and BIIE 0246 treatment reversed the elevated total cholesterol (TC) and low density lipoprotein (LDL-C) level, and reduced high density lipoprotein (HDL-C) level in DM rats. BIIE 0246 may attenuate the increased triglyceride (TG) level in DM rats. In addition, neither BIBP 3226 nor BIIE 0246 treatment produced significant effects on BRS, SBP or HR (P>0.05) in DM rats, even after PE and SNP challenge. However, BIBP 3226 and BIIE 0246 further impaired LVSP, LVEDP, +dp/dtmax and -dp/dtmax.. This study provided us with the evidence that the inhibition of peripheral Y1R and Y2R did not affect impaired BRS but amplified the deterioration of the compromised cardiac function in STZ-induced DM rats with hyperlipidemia.

Topics: Animals; Arginine; Baroreflex; Benzazepines; Blood Pressure; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Experimental; Heart Rate; Hyperlipidemias; Male; Neuropeptide Y; Nitroprusside; Phenylephrine; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Triglycerides

Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system.

Topics: Agouti-Related Protein; Animals; Appetite Regulation; Brain; Cell Line; Energy Metabolism; Female; Glucose Intolerance; Homeostasis; Hyperlipidemias; Hypothalamus; Insulin Resistance; Leptin; Lipid Metabolism; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice; Mice, Knockout; Neuropeptide Y; Obesity; Receptors, LDL; Tumor Suppressor Proteins; Up-Regulation

The purpose of this work was to study the central mechanisms involved in food intake regulation and leptin resistance during gestation in the rat. Sprague Dawley rats of 7, 13, and 18 d of pregnancy [days of gestation (G) 7, G13, and G18] were used and compared with nonpregnant animals in diestrus-1. Food intake was already increased in G7, before hyperleptinemia and central leptin resistance was established in midpregnancy. Leptin resistance was due to a reduction in leptin transport through the blood-brain barrier (BBB) and to alterations in leptin signaling within the hypothalamus based on an increase in suppressor of cytokine signaling 3 levels and a blockade of signal transducer and activator of transcription-3 phosphorylation (G13), followed by a decrease in LepRb and of Akt phosphorylation (G18). In early gestation (G7), no change in hypothalamic neuropeptide Y (NPY), agouti-related peptide (AgRP), or proopiomelanocortin (POMC) expression was shown. Nevertheless, an increase in NPY and AgRP and a decrease in POMC mRNA were observed in G13 and G18 rats, probably reflecting the leptin resistance. To investigate the effect of maternal vs. placental hormones on these mechanisms, we used a model of pseudogestation. Rats of 9 d of pseudogestation were hyperphagic, showing an increase in body and adipose tissue weight, normoleptinemia, and normal responses to iv/intracerebroventricular leptin on hypothalamic leptin signaling, food intake, and body weight. Leptin transport through the BBB, and hypothalamic NPY, AgRP and POMC expression were unchanged. Finally, the transport of leptin through the BBB was assessed using a double-chamber culture system of choroid plexus epithelial cells or brain microvascular endothelial cells. We found that sustained high levels of prolactin significantly reduced leptin translocation through the barrier, whereas progesterone and β-estradiol did not show any effect. Our data demonstrate a dual mechanism of leptin resistance during mid/late-pregnancy, which is not due to maternal hormones and which allows the maintenance of hyperphagia in the presence of hyperleptinemia driven by an increase in NPY and AgRP and a decrease in POMC mRNA. By contrast, in early pregnancy maternal hormones induce hyperphagia without the regulation of hypothalamic NPY, AgRP, or POMC and in the absence of leptin resistance.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Blood-Brain Barrier; Blotting, Western; Body Weight; Cells, Cultured; Eating; Enzyme-Linked Immunosorbent Assay; Female; Hyperlipidemias; Hyperphagia; Hypothalamus; In Situ Hybridization; Infusions, Intraventricular; Injections, Intravenous; Leptin; Neuropeptide Y; Pregnancy; Pro-Opiomelanocortin; Progesterone; Rats; Rats, Sprague-Dawley

Orlistat is an inhibitor of lipase which splits triglycerides into free fatty acides and glycerol. This drug, by inhibiting hydrolysis of triglycerides, is the cause of significant loss of fat in the faeces. 13 obese and 15 nonobese subjects were examined. Obese subjects received orlistat (Xenical, F. Hoffmann La Roche Ltd, Switzerland) 3 x 120 mg/d. Treatment with orlistat for 16 weeks was followed by a significant fall of BMI and MAP, insulinemia, insulin/glucose ratio, leptinemia, serum total cholesterol, triglycerides, HDL-cholesterol and 25-OH-D concentration respectively. Orlistat did not influence significantly serum LDL-cholesterol concentration but unexpectedly increased plasma levels of folic acid, vitamin B12 and NPY.. (1) Monitoring of plasma 25-OH-D levels in obese patients on orlistat therapy seems to be mandatory. (2) In spite of significant changes (in opposite direction) in leptinemia and serum NPY level observed in obese subjects treated with orlistat, presence of a functional relationship between these hormones could not be confirmed.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Carbohydrates; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Enzyme Inhibitors; Female; Hormones; Humans; Hypercholesterolemia; Hyperlipidemias; Insulin; Lactones; Leptin; Lipase; Lipids; Male; Neuropeptide Y; Obesity; Orlistat; Poland; Time Factors; Treatment Outcome; Triglycerides; Vitamins; Weight Loss

To observe the changes of some neuropeptides and the effect of Fusheng powder (FSP) on neuropeptides in rat's brains in a stable cerebral ischemia and reperfusion (I/L) model.. The models of rat's brain injured were established by repeated cerebral I/R in rats with hyperlipidemia. Radioimmunoassay (RIA) was performed to determine the level of neuropeptides.. After 1 day of I/R, compared with the control group, the contents of endothelin-1 (ET-1), calcitonin gene related peptide (CGRP) and neuropeptide Y (NPY) in the model animals were significantly increased by 24.3%, 33.7% and 51.86% respectively, while the level of somatostatin (SS) decreased by 37.86% (all P < 0.01). Meanwhile after FSP treatment, the contents of neuropeptides were alleviated respectively (P < 0.05, P < 0.01). Apart from the ET, the releases of CGRP, NPY and SS were all recovered in different degree after 7 days of I/R.. There were obvious imbalance of neuropeptides in rat's brains after cerebral I/R and the FSP might antagonize ischemic injury of brain through modulating neuropeptides, which may be one of the therapeutical mechanism in treating cerebral vascular diseases with FSP.

Topics: Animals; Brain; Brain Ischemia; Calcitonin Gene-Related Peptide; Drugs, Chinese Herbal; Endothelin-1; Hyperlipidemias; Male; Neuropeptide Y; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury